Disorders of Haemostasis

Question 1

Diapedisis

Answer 1

Minor haemorrhage- Red cells coming out of the gaps almost one by one

Could be fatal in the brain

Question 2

Epistasis

Haemoptasis

Haematemesis

Answer 2

Bleeding into the nostrils

Coughing up blood

Vomiting fresh blood

Question 3

Haemathrosis

Hyphaema

Melaena

Dysentery

Answer 3

Haemorrhage into joints

Bleeding into the anterior chamber of the eye

Bleeding in the upper alimentary tract or swalling blood from resp tract

Diarrhoea containing blood

Question 4

Answer 4

Ecchymoses with a few petechiae and a few purapuras

Question 5

Answer 5

Paintbrush or suffuse haemorrhages

Question 6

Answer 6

Haematoma

Trauma around vulva after farrowing, IV “fishing”

Question 7

Pigments in bruises in stages

Answer 7

Blue purple early on: poorly oxygenated or deoxygenated haemoglobin

Greeny, blue bruise in between stage: Bilirubin and biliverdin

Later stage: Haemosiderin (golden) in macrophages

Question 8

What is the lump left behind by a haematoma?

Answer 8

Once macrophages have gobbled up RBCs, platelets, fibrin, etc. Granulation tissue around the periphery after about 5 days. It will fill the gap where all the blood was with collagen. It will contract down but some can be persistent

Question 9

Where are the most serious haemorrhages no matter the size?

Answer 9

Inside the skull, increases intercranial pressure

Bleeding into the pericardial sac

Retinal bleeding

Bleeding in the brain

Question 10

What is good about an internal bleed?

Answer 10

You can reabsorb and recycle- salvage iron and plasma proteins i.e. haemangiosarcomas of the spleen

Otherwise hypoproteinaemia, iron deficiency, anaemia

Question 11

How much blood can we safely take?

Answer 11

10% of bodyweight

(In a healthy animal you could take 20% but you never know, are they truly healthy)

Beyond 20%= hypovolaemic shock

Beyond 50% loss (trauma) of blood volume quickly almost guarunteed fatal unless someone is standing by with a transfusion bag

Question 12

Causes of haemorrhage

Answer 12

Trauma (first thought), bleeding tumours, aspergillosis (necrotising), bleeding disorder, etc

Question 13

Morphological response to injury

Answer 13

Acute Injury

Vasoconstriction

Primary plug (platelets) (sec/min)

Definitive plug (fibrin) (min/hr)

Fibrinolysis and repair (days)

Question 14

If you didn’t have enough platelets, how long would you bleed for?

Answer 14

Not too long because eventually your body would still form the plug with fibrin

Question 15

Primary Haemostasis

Answer 15

Bleeding immediately after venipuncture, small volume bleeds, petechiae common, haematomas uncommon, bleeding from mucous membranes and skin, bleeding from multiple sites.

Question 16

Answer 16

Primary haemostatic disorder

Question 17

Secondary haemostasis

Answer 17

Delayed bleeding after venipuncture, large volume bleeds, petechiae rare, haematomas (palpable bleeds), bleeding into muscles, joints and/or body cavities, bleeding may be localized, +/- mucosal bleeding

Question 18

Epistasis- is it primary or secondary haemostasis?

Answer 18

Primary or secondary haemostasis

Question 19

Disorder of Primary Haemostasis

Answer 19

After a blood vessel is damaged, instant vasoconstriction (doesn’t help much with preventing a haemorrhage)- need platelets coming in. VW factor becomes important. Platelets releasing cytokines and chemokines- which lures other platelets and then they all adhere to each other. At this point, at the end of the primary platelet plug forming.

** one part of these steps going on, it is never total, but is it enough to prevent bleeding?

Question 20

Thrombocytopenia

Answer 20

Most common in domestic animals- not having enough platelets in circulation

* decreased platelet production (accompanying neutropenias +/- non regenerative anaemias) or increased platelet destruction (premature destruction, esp. immune mediated is the most common mechanism in a dog)*

The next 3 are possible, but unlikely to drop your platelet count low enough to make you bleed: consumption of platelets (something going on when they are being used up, DIC- numerous little bleeds- less dramatic consumption does occur e.g. heartworm, haemangiosarcoma), sequestration of platelets (most platelets are in spleen stored- if spleen or liver enlarged then more platelets remain instead of circulate. OR acute interstitial pneumonias- lots of damage to lots of pulmonary capillaries simultaneously- ones just sequestered in pulmonary capillaries), haemorrhage (lose red cells, leukocytes, and platelets- you have to think, is it caused by the haemorrhage or contributing to the haemorrhage?)

Question 22

Most common thrombocytopenia in cats and in dogs?

Answer 22

Cats- decreased platelet production (bone marrow problem)

Dogs- immune mediated destruction

Question 23

Thrombocytopathies

Answer 23

Platelets not functioning properly

Question 24

Where is vWF unnecessary when there is a bleed?

Answer 24

In capillaries, low blood flow, do not need vWF

Question 25

Where is vWF?

Answer 25

circulating in the blood stream, fibroblasts (mesenchymal cells- naturally express it on their surface)- once you lose the endothelium it is there- do not have to make it, platelets have them in their granules (chocolate chips on the scanning micrograph)

Question 26

Type 1 vWD

Answer 26

>90% of bases in dogs

60% of Doberman pinschers in AUS deemed to be carriers; autosomal recessive (older survey)

Spontaneous bleeding or more commonly bleeding in excess after trauma

Question 27

Type 3 vWF

Answer 27

Scottish Terriers

Negligible vWF in plasma, with all multimers absent

Trauma in homozygotes–> severe haemorrhage

Question 28

How old will a dog be when they first manifest with vWD?

Answer 28

Extremely young- especially with type 2 and type 3-Can be responsible for stillbirths- bleeding out from the umbilical cord postnatally

Type 1 would likely manifest during play when they’re young or a bitch in her first heat (Type 1 2-3 yo)

Question 29

What does vWF do in the blood?

Answer 29

Stabilizes Factor VIII in the blood because it travels with it as a complex- it protects FVIII from degradation by proteases

Question 30

Blood vessel disorders (least common)

Answer 30

* Infectious vasculitis i.e. Rocky Mountain spotted fever (Rickettsia rickettsii) in dogs- damaging lots of vessels simultaneously. Presents as petechiae.

* Fragility of blood vessels- vitamin C deficiency (scurvy) of Guinea pigs**, pigs, and primates- vitamin C is a cofactor for the enzyme that strengthens the crosslinking of collagen- you need that for blood vessel walls otherwise they “seep” a bit

– Cats that develop Cushing’s or poorly controlled Diabetes Mellitus- skin fragility or easy bleeding (hyperadrenocorticism)

Question 31

When do extrinsic and intrinsic pathways start in regards to clotting?

Answer 31

When there is a bleed- extrinsic pathway (shorter) gets started first and then gets shut down with time and with thrombin and intrinsic pathway starts (shuts the extrinsic down)

Question 32

Secondary Haemostasis- what is the most common affecting domestic animals?

Answer 32

Vitamin K antagonism is the most common

Question 33

Haemophilia A, B, C- what factors are deficient? What happens? Who are common dog breeds affected?

Answer 33

A - Inherited deficiency of FVIII (of the intrinsic). B - Factor IX deficiency and C - Factor XI (11) (Haemophilia C usually causes only mild bleeding because factor X can be activated by the extrinsic system)

Can die at a young age of excessive bleeding.

German Shepherds and Vieslas- Haemophilia A

*Devon Rex- autosomal inherited deficiency of a particular enzyme that is involved in the liver in the last step of vitamin K dependent clotting factors (factors II, VII, IX, and X) often bleed severely in the neonatal period– condition can be treated with oral/parenteral (other than orally subcutaneous, or IM, etc.) vitamin K (2, 7, 9 , and 10 if it doesnt add the carboxyl group because deficient in gamma-glutamyl carboxylase- essentially useless)

Question 34

Vitamin K deficiency

Answer 34

Rare, most reported cases in dogs

GI bugs can make vitamin K (though you could get rid of those on longterm antibiotics)

Commercial diets contain lots of vitamin K, liver has a large reserve of vitamin K

Prolonged anorexia or malnutrition could cause or contribute to deficiency

Vitamin K is a fat-soluble vitamin- animals with chronic lipid maldigestion/ malabsorption syndromes may develop vit K deficiency, esp. if also on oral antibiotics- e.g. complete extrahepatic bile duct obstruction, exocrine pancreatic insufficiency, intestinal malabsorption

Question 35

Severe or chronic liver disease- always has to be a consideration because?

Answer 35

The liver makes most of the clotting factors

Question 36

What is vitamin K antagonism?

Answer 36

Anticoagulant rodenticides containing hydroxycoumarins or indandiones, mouldy sweet clover (Melilotus alba) or sweet vernal grass (Anthoxanthum odoratum), overdoes of sulphaquinoxaline (rodenticide), therapeutic coumadins (warfarin meds of owners)

Question 37

Error in notes: Hepatic Parenchymal disease: bleeding due to inadequate synthesis of coagulation factors can be a feature of severe acute hepatopathies or chronic hepatopathies in which the functional mass of hepatocytes has been reduced to?

Answer 37

< 30%

Question 38

Necrosis of hepatocytes–> damage endothelial cells lining hepatic sinusoids–> platelet consumption in haemostasis?

Answer 38

Thrombocytopenia

Question 39

Liver (hepatocytes) is also the source of

Answer 39

Anticoagulants like antithrombin, alpha 2 macroglobulin, alpha 1 protease inhibitor, protein C and protein S; fibrinolytic agents e.g. plasminogen and fibrinolytic inhibitors e.g. alpha 2 antiplasmin

Question 40

Severe hepatic necrosis can trigger what ?

Answer 40

Thrombosis or even DIC (commences with thrombosis in microcirculation and may ultimately lead to haemorrhage)

Question 41

What can plasmin do? When can it occur?

Answer 41

Enzymatically degrade fibrinogen (fibrinogenlysis). Can be excessive fibrinogenlysis–> inability to generate fibrin when needed–> haemorrhage

snake envenomation e.g. Eastern and Western diamondback rattlesnakes, admin of plasminogen activators e.g. t-PA, streptokinase, excessive endothelial release of t-PA e.g. shock, heat stroke, severe tissue trauma

Question 42

Disseminated Intravascular Coagulation

Answer 42

A complex acquired disorder of haemostasis that commences with widespread activation of blood coagulation within the microcirculation and may progress to sustained fibrinolysis and haemorrhage.

You won’t see macroscopic thrombi. Microscopic but damaging because of how many.

Late stage- use up all the clotting factors making all of the thrombi- massive haemorrhage

Question 43

Is DIC a primary or secondary disease?

Answer 43

Always secondary. Always a disease that pushes an animal into DIC.

Question 44

DIC manifestations

Answer 44

Acute, subacute, or chronic

Generalised throughout the body or localised to a specific organ or tissue

Question 45

What are the two major mechanisms that trigger DIC?

Answer 45

* release of tissue factor (factor III) or tissue factor-like procoagulant factors into the circulation

* widespread endothelial injury

Question 46

What is streptokinase?

Answer 46

Plasminogen activator

Question 47

What happens when tissue factor III and/or related procoagulant factors from injured cells (including endothelium) is released?

Answer 47

Activation of the extrinsic system of coagulation

Question 48

What are some probable causes of triggering DIC?

Answer 48

Pancreatic necrosis, tissue trauma, snake envenomation, burns, malignant neoplasia, foetal or placental retention

Question 49

African Swine Fever can cause? Infectious canine hepatitus? Babesia?

Answer 49

DIC

Question 50

What are the two mechanisms from many diseases that can put an animal at risk for DIC?

Answer 50

Any disease with lots of tissue necrosis or vascular injury is at risk of DIC

Question 51

Where is most tissue factor in your body?

Answer 51

Tissues inside cells (Factor III). It is a protease. With lots of necrosis, they are releasing it into the circulation, now at risk for DIC because blood is hypercoagulable. Any disease wher eyou are releasing tissue factor or endothelial cells are presenting it on their surface.

Question 52

What acts like tissue factor but isn’t?

Answer 52

Leukaemias or mast cells if they are releasing their granules, they act as proteases- procoagulants in the blood stream. Blebs of mucous- which triggers a short cut into the coagulation cascade. Some snake venoms automatically activate factor 10 or prothrombin, way down in the clotting pathway.

Question 53

Haemangiosarcomas (vascular endothelial cells)- how does it put an animal at risk of DIC?

Answer 53

often express excess tissue factor on their surface

Question 54

What can circulating trypsin do? (Pancreatic necrosis)

Answer 54

Activate Factor 10 = potential for DIC

Question 55

Gram negative bacteria- as they are dying or dead- part of their cell wall is the endotoxin. A very potent molecule. Tells monocytes and macrophages to make extra tissue factor and express on their surface and release into circulation.

Answer 55

Double wammy for hypercoagubility

Monocytes/ macrophages that are activated by endotoxin, immune complexes, cytokines and anaphylatoxins also release IL-1 and TNF–. increased expression of tissue factor and decreased expression of thrombomodulin (an anticoagulant) by endothelial cell membranes–> activation of extrinsic coagulation and loss of control of coagulation

Question 56

Damaged activated endothelial cell can be distrubed by?

Answer 56

Rocky Mountain Spotted Fever, another virus, endotoxin, etc. Causing them to release vWF and exposing tissue factor on their surface, promoting platelet adhesion, decreasing anticoagulant molecules e.g. thrombomodulin

Question 57

3 general causes of DIC

Answer 57

Massive tissue destruction, sepsis, endothelial disease

Question 58

Phase 1 Hypercoagulability

Answer 58

* Subclinical but you have clinical signs of primary disease

* start to make many abnormal microthrombi

* thrombin generation is still counterbalanced by anticoagulant molecules e.g. antithrombin (AT), thrombomodulin, protein C, protein S etc. BUT your Rocky Mountain spotted fever persists- and now hepatocytes cannot replace the AT quickly enough and you’ll eventually get to a point without checks and balances– then you’ll move into clinical DIC

* hypercoagulability because of excess tissue factor

Question 59

Phase 2 Microthrombosis

Answer 59

* inhibition of fibrinolysis- if you are generating lots of thrombin- cleaves fibrinogen to fibrin- run out of inhibitors so doing it in excess- so they produce plasminogen activator inhibitors- which switches off plasminogen to plasmin- so any fibrin you’re forming sticks around longer than it should (contributor)

* key point: hypercoagulable state where clotting was occuring but still checks and balances- run out of inhibitors- start to form microthrombi

* Where do they occur? Well, where is the primary disease operating?

* i.e. Rocky Mtn spotted fever- could be every organ in your body. OR Haemangiosarcoma in the spleen- might just be in the spleen or in the nodule. UNPREDICTABLE

* How would you know microthrombosis? Dyspnoea, coughing, pulmonary oedema, pulmonary haemorrhage, areas of ischaemia in the lungs, or urea and creatinine and phosphate levels going up, reducing urine formation, anuria, kidneys can shut down, could have seizures, coma, could have a heart attack from blocking coronary arterioles (ischaemia) UNPREDICTABLE

MANY ANIMALS DIE IN PHASE 2 from organs shutting down and becoming dysfunctional

COULD go into shock- which drops BP, impaired venous return. Why would you go into shock? microthrombi blocking little blood vessels. VR decreases, so CO decreases as well.

Question 60

Clotting factors also cause??

Answer 60

They are pro inflammatory. Blood brings in neutrophils- release free radicals and proteases. Switching on systemic inflammatory cascades.

Question 61

What are kinins? And what phase do they kick in during DIC? What do they do to the body?

Answer 61

Bradykinin- vasodilation and increased permeability.

So if you are switching on kinins all over the body. Blood volume is decreasing, BP is decreasing, so generalized hypoxia.

This occurs in stage 2.

Question 62

Phase 3 Haemorrhage

Answer 62

Many animals never get to this point.

Platelet numbers are so low and existing clotting factors are so low, you still have holes to fill from primary disease i.e. Rocky mountain spotted fever. If you see this, you are at the tail end.

Fibrinolysis increased as well (contributing factor). Why? Activation of factor 11 and 12, kalikrein, and – can cleave plasminogen to plasmin giving you breakdown of fibrin. You started making controlled amounts of fibrin, phase 2 out of control, now at this point- you have so many pre cursor molecules activated- so now it is munching some of the fibrin. But the primary disease is still there damaging new blood vessels- you’d need to get it there long enough for blood vessels to repair SO at this point EVERYTHING is favoring HAEMORRHAGE. When plasmin gets switched on, enzymatically breaking down fibrin or fibrinogen- you make fibrin degradation products- they have anticoagulant activity- lots of this debris accumulating in phase 3. So contributes to bleeding tendency.

“Death is coming”